Uremic toxin indoxyl sulfate induces trained immunity via the AhR-dependent arachidonic acid pathway in end-stage renal disease (ESRD).

Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.

Triglyceride-glucose index is an independent predictor of coronary artery calcification progression in patients with chronic kidney disease.

BACKGROUND: Coronary artery calcification (CAC) is highly prevalent in patients with chronic kidney disease (CKD) and is associated with major adverse cardiovascular events and metabolic disturbances. The triglyceride-glucose index (TyGI), a novel surrogate marker of metabolic syndrome and insulin resistance, is associated with CAC in the general population and in patients with diabetes. This study investigated the association between the TyGI and CAC progression in patients with CKD, which is unknown. METHODS: A total of 1,154 patients with CKD (grades 1-5; age, 52.8 ± 11.9 years; male, 688 [59.6%]) were enrolled from the KNOWCKD (KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease). The TyGI was calculated as follows: ln (fasting triglycerides × fasting glucose/2). Patients were classified into tertiles (low, intermediate, high) based on the TyGI. The primary outcome was annualized percentage change in CAC score [(percent change in CAC score + 1)12/follow-up months - 1] of ≥15%, defined as CAC progression. RESULTS: During the 4-year follow-up, the percentage of patients with CAC progression increased across TyGI groups (28.6%, 37.5%, and 46.2% in low, intermediate, and high groups, respectively; p < 0.001). A high TyGI was associated with an increased risk of CAC progression (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.14-3.88; p = 0.02) compared to the low group. Moreover, a 1-point increase in the TyGI was related to increased risk of CAC progression (OR, 1.55; 95% CI, 1.06-1.76; p = 0.02) after adjustment. CONCLUSION: A high TyGI may be a useful predictor of CAC progression in CKD.

Short-term blood pressure variability as a potential therapeutic target for kidney disease.

Short-term blood pressure variability (BPV) measured with ambulatory blood pressure (BP) monitoring has been demonstrated to be significant in predicting various clinical outcomes. Short-term BPV is distinguished from long-term BPV based on the time interval in which BP fluctuations are measured. Increased short-term BPV has been linked to detrimental effects on the microvascular structure and contributes to subclinical organ damage in the heart, blood vessels, and kidneys, regardless of the average 24-h BP levels. Short-term BPV can be defined by various measures, including calculated metrics (standard deviation, coefficient of variation, average real variability, weighted standard deviation, variability independent of the mean) or dipping patterns. Nevertheless, the additional role of short-term BPV beyond the predictive value of average 24-h BPs or established risk factors for cardiovascular disease and kidney disease remains unclear. In particular, longitudinal studies that evaluate the association between short-term BPV and kidney function impairment are limited and no conclusive data exist regarding which short-term BPV indicators most accurately reflect the prognosis of kidney disease. The issue of how to treat BPV in clinical practice is another concern that is frequently raised. This paper presents a review of the evidence for the prognostic role of short-term BPV in kidney outcomes. Additionally, this review discusses the remaining concerns about short-term BPV that need to be further investigated as an independent risk modifier.

Gender-specific discrepancy in subjective global assessment for mortality in hemodialysis patients.

Although subjective global assessment (SGA) is a widely used representative tool for nutritional investigations even among dialysis patients, no studies have examined gender-specific differences in the ability of SGA to predict mortality in hemodialysis (HD) patients. A total of 2,798 dialysis patients were enrolled from clinical research center for end-stage renal disease (CRC for ESRD) between 2009 and 2015. The cohort was divided into two groups based on nutritional status as evaluated by SGA: 'good nutrition' and 'mild to severe malnutrition'. Multivariate Cox proportional regression analyses were performed to investigate gender-specific differences in SGA for mortality among incident and prevalent HD patients. 'Mild to severe malnutrition' was significantly correlated with increased mortality compared with 'good nutrition' for all HD, incident and prevalent HD patients. Compared with 'good nutrition', 'mild to severe malnutrition' was also more significantly associated with increased mortality in male patients in the incident and prevalent HD groups. However, no significant associations between nutritional status evaluated by SGA and mortality were observed for female patients. SGA of HD patients can be useful for predicting mortality, especially in male HD patients. However, SGA alone might not reflect adverse outcomes in female patients.

The additional benefit of weighted subjective global assessment (SGA) for the predictability of mortality in incident peritoneal dialysis patients: A prospective study.

Although subjective global assessment (SGA) is a widely used tool for nutritional investigation, the scores are dependent on the inspectors' subjective opinions, and there are only few studies that directly assessed the usefulness of SGA and modified SGA in incident peritoneal dialysis (PD) patients. A total of 365 incident PD patients between 2009 and 2015 were enrolled and measured with SGA and calculated using serum albumin and total iron binding capacity (TIBC) levels for weighted SGA. Cox analyses were performed to delineate the association between SGA or weighted SGA and all-cause mortality, and a receiver-operating characteristic was conducted to reveal the additional benefit of weighted SGA on predicting adverse clinical outcomes. The Kaplan-Meier curve showed that the cumulative survival rate in patients with "Good nutrition" (G1) was significantly higher compared to those with "Mild to severe malnutrition" (G2). G2 was significantly associated with an increase in the mortality even after adjusting for several covariates compared with G1. Moreover, a 1-unit increase in weighted SGA was also significantly correlated with mortality after adjustment of the same covariates, while G2 was not significantly associated with an increase in the mortality among young-aged (under 65 years) groups. Meanwhile, a 1-unit increase in weighted SGA was significantly related to an increase in mortality in all the subgroup analyses. Furthermore, the AUCs of weighted SGAs in all groups were significantly increased compared with those of SGA alone. In conclusions, the evaluation of nutritional status based on SGA in incident PD patients might be useful for predicting mortality. However, weighted SGA with serum albumin and TIBC can provide additional predictive power for mortality compared with SGA alone in incident PD patients.